The growth and development of breast tumors is heavily regulated by the activation or repression of growth regulatory genes by steroid hormones. Recently, proteins related to steroid hormone receptors, whose ligands are unknown, have been identified and termed orphan receptors. Our lab has actively explored the role of a new orphan receptor, the retinoid-related orphan receptor-alpha (RORalpha), in breast cancer. The RORalpha subfamily of receptors has been shown to cross-talk with and enhance the activity of the estrogen receptor (ER) and thyroid hormone receptor (TR). Since the ER and TR are known mediators of mitogenic signals in breast cancer cells, the enhancement of their activity by RORalpha should provide an enhanced growth-stimulatory signal to breast cancer cells and recent preliminary studies in our lab support this hypothesis. Our studies also suggest that RORalpha can repress the activity of the retinoic acid receptor (RAR), a potent antimitogenic pathway in breast cancer cells. Based on these studies, we will test the hypothesis that RORalpha crosstalks with other steroid hormone receptors to contribute to the proliferation of breast cancer by regulating the expression of specific growth-modulatory genes in breast cancer cells.